PROJECT ABSTRACT Nicotine is the primary addictive constituent in tobacco. For an individual, chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer; even the health of non-tobacco users is negatively affected by second-hand smoke. There are some important sex differences in this addiction and its health consequences. Women on average take less time than men to become nicotine dependent, make fewer attempts to quit smoking, abstain for less time, relapse at higher rates, and benefit less from nicotine replacement therapy. Clearly, enormous gains to the individual and society would come from a better understanding of factors that contribute to nicotine dependence. Environmental stimuli associated with drugs such as nicotine can be powerful modulators of drug-seeking behavior. Another important factor to the development and tenacity of nicotine dependence is the pharmacological effects of nicotine serving as an interoceptive (internal) stimulus entering into a conditioned association with other reinforcers/unconditioned stimuli [USs (peer acceptance, alcohol, work breaks, stress relief)]. Consequently, over time, a smoker has an opportunity to develop a rich appetitive conditioning history with the stimulus effects of nicotine. This acquired reinforcing value likely contributes to the tenacity of the nicotine addiction. Using a newly developed preclinical animal model that innovatively merges interoceptive conditioning with nicotine self-administration, the present application will rigorously test the hypothesis that following an appetitive interoceptive conditioning history with nicotine, the nicotine stimulus will acquire conditioned reinforcing value that exacerbates the persistence of nicotine-taking behavior. To this end, the Specific Aims will examine how such enhancement of drug intake varies with the salience (dose) of the nicotine stimulus (Aim 1), assess the synergy between nicotine and ethanol by using ethanol or sucrose-ethanol solution as the US (Aim 2), and implement an innovative extinction protocol designed to weaken the acquired conditioned reinforcing value of nicotine to a greater extent than just simple non-reinforcement of the target stimulus (Aim 3) in female and male rats.